The invention relates to a fabrication method for formulating pharmaceutical or other bioaffecting agents in small batches or individual forms using a computer-guided system capable of varying parameters and storing the information so that those parameters used in prototyping may be reproduced during fabrication of quantities of any amount. The system is further capable of interfacing with a computer-based learning system.
Modern drug discovery efforts are exploiting at least three core technologies aimed at increasing the efficiency of finding drug leads: genomics, high-throughput screening, and combinatorial chemistry. Research aimed at the human genome is rapidly multiplying the number of disease targets. Screening methods using biological assays can quickly show if a compound is a xe2x80x9chitxe2x80x9d, that is, if it has activity against a target. Combinatorial chemistry methods can produce and help optimize the compounds used in screening. Many pharmaceutical companies view this state-of-the-art technology as being necessary to compete in the market.
On the other hand, the previous or xe2x80x9cclassicalxe2x80x9d approach to drug discovery involved:
A) synthesizing molecules known to be related to natural or other synthetic structures having some or all of the desired pharmaceutical activity;
B) testing small quantities of purified or otherwise defined chemical compositions in biological assays;
C) selecting a xe2x80x9clead compoundxe2x80x9d to continue investigating, which may include human clinical trials; and,
D) redesigning the compound an redevelopment of a xe2x80x9csecond leadxe2x80x9d.
The classical process was prone to requiring several decades of development time in order to learn whether the candidate molecule or substance would succeed or fail. Companies with larger collections of compounds or compound libraries have had an empirical advantage.
The next set of innovations included the miniaturization of both the activity assays and the synthetic processes for generating a large number of test candidates. Combinatorial chemistry, broadly defined as the generation of numerous organic compounds through rapid simultaneous, parallel or automated synthesis, is changing how chemists create chemical libraries and is expected to change the speed at which drugs are found. Combinatorial chemistry techniques rely on the alteration of simple steps or ingredients in a sequence of steps to randomly produce a series of related test candidates or prototypes. These candidates are then screened for presence of desired biological activity. The so called xe2x80x9chigh throughput screensxe2x80x9d rely on semiautomated and usually miniaturized versions of traditional calorimetric, potentiometric, fluorometric, radiometric, or other signal generating systems coupled to a desired biological marker or activity. The use of biological systems, such as xe2x80x9cphage display librariesxe2x80x9d, has allowed for systems other than mechanized synthesis to be used in generating the raw material to screen.
The advents of combinatorial chemistry and rapid in vitro screening have, therefore, dramatically increased the efficiency of the chemist in discovering new drug entities. However, at the moment, there are no known techniques for handling the rational and rigorous formulation development of drug delivery systems for the plethora of new compounds, other than substantially increasing headcount and requisite equipment. Traditional oral dosage form processing requires a multitude of sequential steps, which may include powder mixing and blending, wet granulation and drying, lubrication. compression, and coating. This approach to formulation development can be characterized as a linear method. Consequently, development of successful formulations is very time consuming and severely limits the ability of pharmaceutical companies to expeditiously bring new drugs to the market.
The formulation scientist has traditionally relied on training and experience to formulate a novel, active agent of known chemical and physical properties. The scientist has to take into consideration many characteristics of the active agent in designing a dosage form, including suitable route of administration, drug release, distribution, metabolism, elimination, stability, and compatibility with excipients. Consequently, the formulation scientist has a large number of criteria to satisfy and optimize. Furthermore, the formulation must be stable and amenable to scale-up in order to produce commercial quantities.
One of the problems facing formulation scientists is that the production and testing of small batches of formulations, such as tablets, is as time consuming as the production of large batches. Therefore, in order to make batches of tablets, for example, in sufficient quantity for clinical and stability testing, a single limited production has to be completed.
Another problem of the prior art is with respect to the fabrication of structures with designed pore or channel structures. It has been a challenging task even with additive manufacturing processes such as 3DP. Structures with radial or vertical channels of hundreds of microns in diameter were fabricated; however, the formation of narrower and tortuous internal structures were best affected by the use of a sacrificial material. One common practice in the construction of tissue engineering matrices was the use of mixtures of water soluble particulates (sodium chloride) with non-water soluble polymers dissolved in a solvent to fabricate specimens. The salt particles were leached out of the device with water to reveal a porous structure. While this technique was used in fabricating a network of pores, control of pore architecture was lost.
The invention relates to a solid free-form fabrication method to rapidly fabricate different prototypes of drug delivery systems or medical devices in small batches or individual forms using a computer-guided system to vary the composition and structure in order to optimize the product and the manufacturing process, and which process is immediately scalable.
In another aspect, the invention provides for an Expert System for recommending the different compositions and designs of pharmaceutical formulations or s medical devices. The invention further allows for formulation of active-containing dosage forms in small batches or individual forms that have different rates of release of the active agent.
The system of the present invention allows the formulator to make only the required number of units of a prototype necessary for the desired tests. This is accomplished by using computer-controlled processes, such as solid free-form fabrication (SFF) techniques. The use of computer-aided manufacturing techniques allows the same prototype to be reproduced in any batch size for further testing or for commercialization, provided the same sequence of machine instructions is used. Furthermore, such processes allow fabrication of several different prototype designs in a short time. This significantly reduces the development time of new products compared to conventional technologies, such as tablet compression, which translates into huge cost savings for companies.
The system further allows extremely small batches, even individual items, to be fabricated with known composition within a single manufacturing run. Therefore, biological and stability testing can be run economically and expeditiously in parallel allowing for the rapid screening of prototype formulations to match the rapid selection of prototype agents available for further development work.
The present invention takes advantage of a rapid manufacturing process, which affords the possibility of rapid prototyping for that manufacturing process. The principle by which this process works is that a formulator designs a dosage form or medical device on a computer workstation using a computer aided design (CAD) software. The workstation then converts the information into machine instructions that would allow fabrication of the CAD-generated 3-D object using suitable materials, generally by building the object layer-by-layer.
SFF is an example of a computer-aided manufacturing process suitable for practicing the teachings of this invention. This process allows a high degree of design flexibility, not only in terms of macroscopic architecture, but most importantly, in composition, microstructure and surface texture within the part being manufactured. The process is easily scaleable, permitting quantities ranging from pre-production prototyping through to manufacturing volumes to be made using a single process. These factors distinguish this unique process from other fabrication approaches and make it ideally suited for manufacturing clinical supplies where materials and design play critical roles in product differentiation (with matching placebos), where shortened product lead-times are of critical strategic advantage, where traditionally large quantities of valuable GMP material are severely limited, and where product/process validation underlies the ability to gain product marketing approval and assure patient safety. A specific example of an SFF process is three dimensional printing (3DP) in which drugs are delivered through a printhead into a bed of powdered excipient blend, and the particles are xe2x80x9cgluedxe2x80x9d together into three dimensional shapes using suitable polymers or binders. An unlimited variety of architectures can be achieved using this technique ranging from simple tablet, capsule, caplet, and rod like shapes for dosage forms to complicated macro and micro architectures for medical devices. Furthermore, the prototypical dosage forms and medical devices, which are produced for clinical supplies, can also be fabricated in production quantities without changing the process. This simplifies the transition from formulation development to manufacturing with faster, less costly scale-up and prescribed validation of production. Numerous production steps are also consolidated into one machine resulting in savings in plant design, capital costs and space requirements. These features minimize design-related compromises and reduce the cost and time normally associated with traditional processes.
The FDA requires a bioequivalence study for a drug delivery formulation if there is a change in composition, process, scale, or site of manufacturing. Several bioequivalence studies are usually performed during product development and scale-up stages of pharmaceutical dosage forms using conventional manufacturing technologies. If the methods taught by this invention are used, the composition and the process parameters can be kept the same, and because each unit is reproducibly fabricated, scale is inconsequential. Thus, it is anticipated that by using the methods of this invention, the number of bioequivalence studies performed during a product development program can be significantly reduced, thereby reducing the time and expenses incurred.
Another significant advantage offered by the use of solid free form fabrication techniques is that toxic or potent compounds can be safely incorporated in an xe2x80x9cexcipient envelopexe2x80x9d, thereby minimizing worker exposure. Altering release rate or sequence of release of combination products is also easily accomplished through the use of suitable polymers. All of these adjustable parameters can be secured for future reference and guidance through the adoption and maintenance of an xe2x80x9cExpert Systemxe2x80x9d, where the use of artificial intelligence can speed up excipient and binder selection, as well as build strategies, including geometry, texture, shape, and binder addition rates. In the simplest form, the Expert System will comprise a suitable database of formulations and an inference engine capable of predicting new formulations based on predefined rules.